Aging is associated with white matter (WM) changes. These changes are most prominent in frontal and prefrontal regions. This study focuses on the role of frontal WM changes in late life depression as this disorder is associated with abnormal limbic and dorsal cortical function that may be perpetuated by WM abnormalities interfering with the reciprocal regulation of these systems. Accordingly, the study seeks to identify aging-related microstructural WM abnormalities contributing to poor outcomes of depression. Its aims have evolved from preliminary findings suggesting that aging-related frontal system dysfunction contributes to poor and unstable treatment response of depression, disability, and executive dysfunction. The study will use diffusion tensor imaging (DTI) to assess fractional anisotropy (FA), a measure of microstructural WM abnormalities, to test the hypotheses that FA lateral to the anterior cingulate is associated with: a.) limited change in depressive symptoms and poor response and remission rate of late life major depression; b.) limited change in disability; and c.) executive dysfunction. These hypotheses will be tested in a sample of 120 subjects with major depression stratified according to age (65-74 and 75-84 years) and executive dysfunction (Stroop), who will undergo a 12-week, controlled, open citalopram trial with a target daily dose of 30 mg after a 2 week drug washout, placebo lead-in. The subjects will have MR scanning and a systematic comprehensive evaluation of psychopathology, neuropsychological functions, functional status and clinical parameters that influence the course of depression (baseline, 8 weeks, and 12 weeks). Depressive symptomatology, functional status, and side effects will be rated weekly. The heuristic significance of the proposed study is that it may localize and quantify for the first time aging related WM abnormalities contributing to poor outcomes of late life depression. The clinical significance of the proposed study is that it can guide research leading to physiologically meaningful, novel antidepressant therapies aimed at aging-related frontal system dysfunction. [unreadable] [unreadable]